CS213395B2 - Method of making the derivatives of 1-phenyl-2,5-cyclohexadien-1-ethylamine - Google Patents

Description

The present invention relates to a process for the preparation of novel 1-phenyl-2,5-cyclohexadiene-1-ethylamine derivatives of the general formula I

in which

R ¹ represents hydrogen or methyl,

R ² represents hydrogen, methyl or ethyl,

R ³ represents a methyl group or a group ethvlovou

R ⁴ is hydrogen or methyl, wherein at least one of R ¹ and R ⁴ is hydrogen, including optically active antipodes of such compounds containing an asymmetric carbon atom, as well as their acid addition salts.

Accordingly, the present invention provides a process for the preparation of novel 1-phenyl-2,5-cyclohexadiene-1-ethylamine derivatives, including their optical antipodes, acid addition salts of these compounds, which compounds have valuable pharmaceutical properties and can be used as active ingredients pharmaceutical preparations suitable for relieving painful conditions.

According to the invention, the 1-phenyl-2,5-cyclohexadiene-1-ethylaimine derivatives of the formula I and their acid addition salts are prepared by not reacting the compounds of the formula II

in which

R ¹ and R ⁴ are as defined above, and X represents a leaving "group, with amines of the general formula III

R ² /

HN \

R ³ (III) ^w and ^G _x PH with CM in which '* - _: *'

R ² and R ³ are as defined above, - - thereafter optionally -Z-twisted racemates? T split into the optically active antipodes and a product obtained is optionally converted to an addition half s- acid.

The reaction according to the invention is preferably carried out in an inert organic solvent such as toluene, benzene, xylene, mono-glyme or diglyme and at a temperature between 120 and 180 ° C. Preferably, the reaction is carried out under pressure, for example at 1 to 4 MPa. Suitable leaving group X is chlorine, bromine, iodine, methyl or tosyl, especially methyl.

The starting materials of the formula II in which R1 is hydrogen can be obtained by starting esters of the formula IV

in which

-R 4 is as defined above, and

R is lower alkyl, reduced to an alcohol of formula V

in which

R 4 is as defined above and is further esterified.

Compounds of formula (IV) may be obtained by reacting biphenyl in the presence of lithium or calcium and ammonia with a chloro-acetic acid ester of formula (VI)

R4 i

Cl — CH — COOR, (VI) wherein

R is lower alkyl and

R4 is as defined above.

Výchcizí compound of formula II wherein R ¹ represents a methyl group, can be obtained from starting materials of formula V in that said compound is oxidized with sulfur trioxide pyridine in dimethyl sulfoxide, to the resulting aldehyde is treated with methyl magnesium iodide or methylmagnesumbromideim and the resulting compound of of formula VII

(and 1 / (VID

in which

R 4 as defined above, is esterified to give the starting material of formula II wherein R 1 is methyl.

The starting amines of formula III are known.

The reaction products formed in -vzorce I fortaě racemates can .známými se methods, e.g., cleavage of ^one of the racemates of optically -aktivními acids separated into antipodes.

The compounds of the formula I can be converted into the corresponding salts by treatment with inorganic or organic acids, in particular pharmaceutically usable salts. Examples of acids that form pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, tartaric acid, sinic acid, phosphoric acid, tartaric acid, citric acid, maleic acid, ascorbic acid, formic acid, acetic acid, succinic acid, methane, benzene. - and p-toluenesulfonic acid, etc.

The compounds of the invention are - as - have been shown in the known writhing test, the resp. 'Kaolin test' - analgesically effective. Their intensity is somewhat lower than that of codeine and propoxyphene, but greater than aminophenazone and acetylsalicylic acid. Compared to casein and propoxyphene, however, the compounds according to the invention are characterized by weaker undesirable side effects - in particular lower or non-existent addictiveness. The compounds of the invention may therefore be used in the treatment of pain. The dosage can vary within wide limits and, of course, can be adapted to the individual circumstances in each individual case. In general, a single dose of 100 to 300 mg and a daily dose of 400 to 1200 mg can be used for oral administration.

Of particular interest are compounds of formula I p

a) R 1 = r 4 = h and R 2 = R 3 = CH 3 J N, N -dimethyl-1 - (1 - 6, 6-tyl-2,5-cyclo-4-ol) ^ -1-ethylaminin)

b) R1 = R4 = H and R2 = R5 = C2H5 (N, N-diethyl-1-phenyl-2,5-cyclohexadiene-1-e-thylamine)

c) R 1 = CH 3, R 4 = H and R 2 = R 3 = CH 3 (and -N, l-trimethyl-l-phenyl-2,5-cyclohexadiene-1-ethylamine), with very particular preference the compound of (a) is preferred.

The compounds of the invention may be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example in the form of suppositories, topically or percutaneously, for example in the form of ointments, creams, jellies, solutions, or parenterally, for example in the form of injectable solutions.

For the manufacture of tablets, coated tablets, dragees and hard gelatine capsules, the compounds of the invention may be formulated with pharmaceutically inert, inorganic or organic excipients. As such excipients, lactose, net maize starch, derivatives thereof, talc, stearic acid or its salts, etc. can be used, for example, for tablets, dragees and hard capsules.

For soft gelatin capsules, suitable as waxes, fats, semi-solid and liquid polyols, etc .; however, depending on the state of the active substance, no excipients are required at all in soft gelatine capsules.

Water, polyols, sucrose, invert sugar, glucose and the like are suitable as excipients for the production of solutions and syrups.

For injection solutions, water, alcohols, polyols, glycerin, vegetable oils, etc. are suitable as excipients.

For suppositories, further for topical or percutaneous dosage forms, natural or susceptible oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as auxiliary substances.

The pharmaceutical preparations may additionally contain preservatives, co-solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for affecting the osmotic pressure, buffers, coatings or antioxidants. They may also contain other therapeutically valuable substances.

In the following examples, temperatures are given in degrees Celsius.

Example 1

To 600 ml of absolute condensed ammonia was added at -33 ° with 15.4 g (0.1 mol) of biphenyl in 300 ml of absolute ether. Thereafter, 1.67 g (0.24 mole) of lithium 6-wire (cut into approximately 2 cm long pieces degreased with cyclohexane) was added at -70 ° with stirring over 15 minutes. The reaction mixture was stirred at -33 ° for 1 hour. 26.0 g (0.24 mol) of chloroacetic acid methyl ester (freshly distilled) in 100 ml of absolute ether are then added at -70 DEG over a period of 35 minutes, whereupon the dark-red color of the reaction mixture turns yellow. 13.0 g (0.24 mol) of ammonium chloride are then added and the ammonia is distilled off. 200 ml of distilled water are added and the phases are separated. The ether phase is washed with 2 N aqueous hydrochloric acid solution and 2 N aqueous sodium bicarbonate solution. The aqueous phases are further extracted with ether and the combined ether phases are dried over sodium chloride and sodium sulfate, filtered and concentrated completely. From the residue 1.5 g was distilled at 4 Pa. The transition fraction - at 89 ° contains 1-phenyl-2,5-cyclohexadiene-1-acetic acid methyl ester.

To a solution of 11.4 g (0.3 mol) of lithium aluminum hydride in 1150 ml of absolute ether was added dropwise a solution of 68.5 g (0.3 mod) of methyl 1-phenyl-2,5-cyclic ester with stirring. of hexadiene-1-acetic acid in 250 ml of absolute ether. The reaction mixture was stirred for 1 hour. 50 ml of ethanol are then carefully added, followed by 50 ml of water. The mixture was filtered and the residue on the filter was washed with ether. The phases were separated and the combined ethereal solutions were evaporated to dryness. A crystalline liquid is obtained which is recrystallized from a mixture of benzene and hexane. The obtained 1-phenyl-2,5-cyclobexadiene-1-ethanol has a melting point of 58-59 °.

g (0.05 mol) of this product is dissolved in 70 ml of absolute dimethylsulfoxide. 44 ml of triethylamine were then added. 24 g (0.15 mol) of sulfur trioxide-pyridine complex in 100 ml of absolute dimethylsulfoxide are then added dropwise with ice-cooling. After stirring at room temperature for 1 hour, the reaction mixture was worked up as follows: The reaction mixture was poured into water and extracted twice with ether. The ether phases were washed with 3 N aqueous hydrochloric acid solution, washed with water until neutral, dried, filtered and concentrated. An oily product is obtained which is chromatographed on 200 g of silica gel using a 3: 1 mixture of petroleum ether and ether as the eluent. 1-Phenyl-2,5-cyclohexane-1-acetaldehyde is obtained as an oily product.

2.4 g (0.1 mol) of magnesium shavings were introduced and 14.2 g (0.1 mol) of methyl iodide in 15 ml of absolute ether were added dropwise. The mixture was heated at reflux for 1 hour, then cooled. and filtered through glass wool. The filtrate was added dropwise to a solution of 13 g (0.065 mole) of 1-phenyl-2,5-cyano-benzalealeneacetaldehyde in 50 ml of p-butyl ether. After refluxing for 3 hours, the reaction mixture is worked up as follows: add about 2 N aqueous ammonium chloride solution and shake the mixture. The aqueous phase was further extracted with ether. The combined organic phases are washed with water, dried over sodium sulphate, filtered and concentrated. The crude product is chromatographed on 260 g of silica gel using petroleum ether / ether (1/1) as eluent. Α-Meteyl-1-phenyl-2,5-cyclohexadiene-1-ethanol is obtained as an oily product.

g (0.037 mol) of α-methyl-1-phenyl-2,5-cyclohexadiene-1-ethanol are dissolved in 50 ml of pyridine and 6.4 g (0.049 mol) of mesyl chloride are added dropwise at 0-5 °. After stirring at room temperature for 2 hours, the reaction mixture was worked up as follows: ice was added to the reaction mixture and extracted with ether. The ether phase is washed with a 3 N aqueous hydrochloric acid solution, then washed neutral, dried and concentrated. The crude product obtained is chromatographed on 100 g of silica gel with ether / petroleum ether (1: 1). Gets. is an oily product which crystallizes cold. Crystallization from methylene chloride / hexane gave methanesulfonic acid 1-methyl-2- (1-phenyl-2,5-cyclohexadien-1-yl) ethyl ester, m.p. 51-53 °.

To 1.5 g (5.14 in addition) of 1: methanesulfonic acid ethyl-2- (1H-enyl-2,5-cyclohexadien-1-yl) -ethyl ester in 5 ml of toluene was added at -10 ° C. 1 ml (about 3 equivalents). condensed dimethylamine. The reaction mixture is then held at 150 ° C in a pressure vessel for 16 hours. The reaction mixture was cooled and worked up as follows: the toluene phase was washed with water, concentrated, ether and 3 N aqueous hydrochloric acid were added, and the mixture was shaken. The aqueous extract was basified with concentrated ammonia and extracted again with ether. An oily residue is obtained which is chromatographed on a thick layer using a 10: 1 mixture of methylene chloride and methanol as solvent. Α, N, N-trimethyl-1-phenyl-2,5-cyclohexadiene-1-ethylamine is obtained, which is converted to the hydrochloride by conventional means.

Example 2 g (0.1 mol) of 1-phenyl-2,5-cyclohexadiene-1-acetic acid methyl ester are dissolved in 250 ml of absolute tetrahydrofuran and the solution is cooled to about -70. 1 g of 18-trans-6-ether, 19 g (0.17 mol) of potassium tert-butoxide and 28 ml (0.45 mol) of methyl iodide are then added. The mixture was stirred overnight at -70 ° and then worked up as follows: The reaction mixture was poured into ice water and extracted with ether. The organic phases are washed with water, dried over magnesium sulphate, filtered and the filtrate is completely evaporated. The oil obtained is filtered through a silica gel column. The thus obtained 2- (1-phenyl-2,5-cycloleadien-1-yl) -propionic acid methyl ester was used for the next reaction step without further purification.

3 g (0.079 mol) of lithium aluminum hydride in 100 ml of absolute ether are introduced and 18.9 g of the product obtained above in 80 ml of ether are added dropwise. After a reaction time of two hours at room temperature, the reaction mixture is worked up as follows: the excess lithium-malem-mintomhydride is quenched with alcohol and then with water. After filtration, the phases are separated and the ether phase is washed with water, dried over magnesium sulphate, filtered and concentrated. A clear oil is obtained which. The reaction mixture is chromatographed on silica-ageto using a mixture of petroleum ether and ether (1: 1) as eluant. It is obtained. (3-Methyl-1-phenyl-2,5-cyclobenzadiene-1-ethanol) as an oily product, g (70 mmol) of the above product is dissolved in 200 ml of pyridine and 8 is added dropwise. 8 ml (113 mmol) of methanesulfonic acid chloride After stirring at room temperature for 6 hours, the reaction mixture is worked up as follows: ether and water, a 3 N aqueous hydrochloric acid solution are added to the reaction mixture, then washed again with water, dried over sulfate The crude product obtained is chromatographed on silica gel using petroleum ether and ether (1: 2) to give oily 2- (1-O, 1,2-2,5-cyclohexanedien-1-ol). -yl) methanesulfonic acid ester.

9.4 g (32.2 mmol). of this product is dissolved in 8 ml of toluene. 4.1 ml was added at -10 °. (about 3 equivalents) of condensed methylamine. The reaction mixture is then held in a pressure vessel at 150 ° C for 24 hours. 8.2 ml of methylamine are then added and the reaction mixture is maintained at 150 DEG C. for a further 24 hours. Thereafter, the reaction mixture was concentrated, ether and a 3N solution of chloroic acid were added thereto, and the mixture was shaken. After filtering off the deposited crystals, the aqueous phase was re-alkalized and extracted with methylene chloride. The crystalline fraction was also washed with methyl chloride and aqueous sodium hydroxide solution. The combined methylene chloride phases are washed with water until neutral, dried over sodium sulfate, filtered and concentrated. The oily product thus obtained is chromatographed on 120 g of aluminum oxide (neutral) using a mixture of methylene chloride and methanol (10: 1) as the eluent. N, N-dimethyl-1-phenyl-1,2,5-cyclohexadiene-1-ethylamine is obtained. The hydrochloride produced in a conventional manner has a melting point> 250 °.

Example 3 g (27.4 mmol) of methanesulfonic acid 2- (1-phenyl-2,5-cyclohexadlen-1-yl) propyl ester are dissolved in 10 ml of toluene. 8.4 ml was added at -10 ° C. (about 3 equivalents) of condensed dlethylamine. The reaction mixture is then held at 150 ° C in a pressure vessel for 25 hours. After cooling, the toluene sulfone phase is washed with water, concentrated, ether and 3 N aqueous hydrochloric acid are added and the mixture is shaken. The aqueous phase was basified with concentrated aqueous ammonia. and extracted again with ether. The combined ether phases were. dried over sodium sulfate, filtered and concentrated. An oily product is obtained which is chromatographed on silica gel using a mixture of - methylene chloride and - methanol (1.0: 1) as eluent. 3-Methyl-N, N-diethyl-4-phenyl-2,5 ' ⁽ cyclohexadiene-1-ethylamine) is obtained as an oily product which is converted to the hydrochloride in the usual manner, which recrystallizes from a mixture of ethanol and ether. 132-137 °.

Example 1 a d 4

18.6 g (0.162 mol) of methanesulfonic acid chloride were added dropwise while stirring and cooling to a solution of 27 g (0.135 mol) of 1-phenyl-2,5-cyclohexadiene-1-ethanol in 270 ml of absolute pyridine. After stirring at room temperature for 3 hours, about 250 mL of water was added to the mixture. The precipitated product is filtered off, washed with water and dried. The crude product was recrystallized from benzene / hexane to give methanesulfonic acid 2- (1-phenyl-2,5-cyclohexadien-1-yl) ethyl ester as colorless crystals, m.p. 64-65.

100 g of this product is dissolved in 600 ml of toluene. 70 ml (about 3 equivalents) of condensed dimethylarinine are added at -10 DEG C. and the reaction mixture is heated to 150 DEG C. in a pressure vessel for 16 hours. The reaction mixture is worked up as follows: the toluene solution is washed with water and concentrated completely. The oil obtained was redissolved in benzene and this solution was extracted with a 3 N aqueous hydrochloric acid solution. The aqueous phase was re-basified with concentrated ammonia and extracted with ether. The combined ether extracts were washed with water, dried over sodium sulfate, filtered and concentrated. Crude N, N-dimethyl-1-phenyl-2,5-cyclohexadiene-1-ethylamine is obtained, which is converted to (1: 1) maleate in the usual manner.

Example 5

In an analogous manner to that described in Example 4, methanesulfonic acid 2- (1-phenyl-2,5-cyclohexadien-1-yl) ethyl ester was reacted with methylamine. The crude product obtained is converted to the hydrochloride in a conventional manner, which is recrystallized from isopropanol. N-Imethyl-1-phenyl-2,5-cyclohexadiene-1-ethylaminohydride is obtained, m.p. 172-173 °.

EXAMPLE 6 g (0.31 mol) of methanesulfonic acid 2- (1-phenyl-2,5-cyclohexadien-1-yl) -ethyl ester were dissolved in 600 ml of toluene. 95 ml (about 3 equivalents) of diethylaimine are then added and the reaction mixture is heated to 150 DEG C. in a pressure vessel for 16 hours. The work-up was carried out as described in the second part of Example 4. Crude N, N-diethyl-1-phenyl-2,5-cyclopentadiene-1-ethyl was obtained ^. a <min, which is dissolved in ether and by treatment; of hydrogen chloride is converted to the hydrochloride. Recrystallization from methylene chloride / ether gave the hydrochloride, m.p. 134-136

The following examples illustrate galenic preparations:

Example A

Hard gelatine capsules

(a) composition:

N, N-dimethyl-1-phenyl-2,5-cyclic * hexadiene-1-ethylamine maleate 100.0mg crystalline lactose 102.0mg white corn starch 45.0mg talc 10.4mg magnesium stearate 2.6mg

260.0 mg

(b) production:

The active ingredient is mixed with corn starch, talc and magnesium stearic acid, sieved through sieve ¹ , lactose is added, mixed again and sieved. The powder mixture is filled into size # 1 capsules.

Example В

Tablets

(a) composition;

N, N-dimethyl-1-phenyl-2,5-cyclohexadiene-1-ethylamine maleate 300.0mg crystalline milk sugar 75.0mg white corn starch 60.0mg

Primejel ^R (sodium carboxymethyl starch) 12.0mg magnesium stearic acid salt 3.0mg

450.0 mg

(b) production:

The active ingredient is mixed with lactose in about a portion. corn starch, the mixture is processed with winter-colored corn starch, granulated, dried and sieved. Primojel and magnesium stearic acid salt are admixed with the granulate and compressed into tablets weighing <450 mg.

Claims (2)

A process for the preparation of 1-phenyl-2,5-cyclohexadiene-1-ethylamine derivatives of the general formula I wherein: R1 is hydrogen or methyl, R ² represents hydrogen, methyl or ethyl group ·, R ³ represents methyl or ethyl, and R4 is hydrogen or methyl, wherein the residues R1 and ^R4 at least one: hydrogen, including the optically active antipodes of those compounds which contain an asymmetric carbon atom as well. an acid addition salt thereof, characterized in that the compound of formula (II): wherein: R and R ⁴ are as defined above. · And X is a leaving group, treated with an amine of formula III R2 / HN, (III) in which R2 and ^R3 are as defined above and, if desired, the racemic compound rolzštěpí the optically active antipodes and a product obtained is optionally converted into an acid addition salt-u. 2. A process according to claim 1 for the preparation of N, N-dimethyl-1,1-phenyl-2,5-cyclohexadiene-1-ethylalamine or a pharmaceutically acceptable acid addition salt thereof, which comprises: wherein R 1 and R ⁴ are hydrogen, and X is as defined. as described in item 1, treated with dlmethylamine and optionally the free base obtained is converted to a pharmaceutically acceptable acid addition salt.